Field of the Invention
This invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease. This invention also relates to pharmaceutical compositions comprising such compounds as well as methods for inhibiting release of xcex2-amyloid peptide.
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Glenner, et al., xe2x80x9cAlzheimer""s Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Proteinxe2x80x9d, Biochem. Biophys. Res. Commun., 120:885-890 (1984).
2 Glenner, et al., xe2x80x9cPolypeptide Marker for Alzheimer""s Disease and its Use for Diagnosisxe2x80x9d, U.S. Pat. No. 4,666,829 issued May 19, 1987.
3 Selkoe, xe2x80x9cThe Molecular Pathology of Alzheimer""s Diseasexe2x80x9d, Neuron, b:487498 (1991).
4 Goate, et al., xe2x80x9cSegregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer""s Diseasexe2x80x9d, Nature, 349:704-706 (1990).
5 Chartier-Harlan, et al., xe2x80x9cEarly-Onset Alzheimer""s Disease Caused by Mutations at Codon 717 of the xcex2-Amyloid Precursor Proteing Genexe2x80x9d, Nature, 353:844-846 (1989).
6 Murrell, et al., xe2x80x9cA Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer""s Diseasexe2x80x9d, Science, 254:97-99 (1991).
7 Mullan, et al., xe2x80x9cA Pathogenic Mutation for Probable Alzheimer""s Disease in the APP Gene at the N-Terminus of xcex2-Amyloid, Nature Genet., 1:345-347 (1992).
8 Schenk, et al., xe2x80x9cMethods and Compositions for the Detection of Soluble xcex2-Amyloid Peptidexe2x80x9d, International Patent Application Publication No. WO 94/10569, published May 11, 1994.
9 Selkoe, xe2x80x9cAmyloid Protein and Alzheimer""s Diseasexe2x80x9d, Scientific American, pp. 2-8, November, 1991.
10 Losse, et al., Tetrahedron, 27:1423-1434 (1971).
11 Citron, et al., xe2x80x9cMutation of the xcex2-Amyloid Precursor Protein in Familial Alzheimer""s Disease Increases xcex2-Protein Production, Nature, 360:672-674 (1992).
12Hansen, et al., xe2x80x9cReexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Killxe2x80x9d, J. Immun. Meth., 119:203-210 (1989).
13 P. Seubert, Nature (1992) 359:325-327
14 Johnson-Wood et al., PNAS USA (1997) 94:1550-1555 Tetrahedron Letters, 34(48), 7685 (1993))
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
Alzheimer""s Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down""s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the xcex2-amyloid peptide (MAP) or sometimes Axcex2, Axcex2P or xcex2/A4. xcex2-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,8292.
Molecular biological and protein chemical analyses have shown that the xcex2-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that xcex2-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the xcex2-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of xcex2-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier-Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the xcex2-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP znd subsequent deposition of its xcex2-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other xcex2-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting xcex2-amyloid peptide release and/or its synthesis in vivo.
This invention is directed to the discovery of a class of compounds which inhibit F-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The class of compounds having the described properties are defined by formula I below: 
wherein R1 is selected from the group consisting of
a) alkyl, alkenyl, alkcycloalkyl, phenyl-(R)m-, naphthyl-(R)m- wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1, cycloalkyl, cycloalkenyl, 3-pyridyl, 4-pyridyl and heteroaryl, other than 3- and 4-pyridyl, of 3 to 10 atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen wherein the heteroaryl group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalxoxy, and thioaryloxy with the proviso that for such heteroaryls when there is at least one nitrogen heteroatom, there is also at least one oxygen and/or sulfur heteroatom;
(b) a substituted phenyl group of formula II: 
wherein R is alkylene of from 1 to 8 carbon atoms,
m is an integer equal to 0 or 1,
Ra and Raxe2x80x2 are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl;
Rb and Rbxe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cyano, cycloalkyl, halo, heteroaryl, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and xe2x80x94C(O)R4 where R4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy; and
Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and where Rb and Rc are fused to form a methylenedioxy ring with the phenyl ring; and
when Rb and/or Rbxe2x80x2 and/or Rc is fluoro, chloro, bromo and/or nitro, then Ra and/or Raxe2x80x2 can also be chloro; and
(c) 1- or 2-naphthyl-(R)m- substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1;
R2 is selected from the group consisting of hydrogen, alkyl, phenyl, alkylalkoxy, alkylthioalkoxy; and
R3 is selected from the group consisting of xe2x80x94(CH2)nCR10R5R6 wherein n is an integer equal to 0, 1 or 2, R5 and R6 are independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl Heterocyclic, xe2x80x94NR7R8 where R7 and R8 are independently hydrogen or alkyl and xe2x80x94COOR9 where R9 is alkyl, and further wherein R5 and R6 can be joined to form a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, and a heterocyclic group, and when R5 and R6 do not join to form an aryl or heteroaryl group, then R10 is selected from hydrogen and alkyl with the proviso that when n is zero, then R10 is hydrogen and when n is greater than zero and R5 and R6 are joined to form an aryl or heteroaryl group, then R10 becomes a bond within that group;
X is oxygen or sulfur;
Xxe2x80x2 is hydrogen, hydroxy or fluoro;
Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group, and
pharmaceutically acceptable salts thereof
with the provisos that:
when R1 is phenyl, R2 is xe2x80x94CH(CH3)CH2CH3, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R3 is not xe2x80x94CH2CH3 or xe2x80x94CH2CH(CH3)2 
when R1 is phenyl, R3 is xe2x80x94CH2CH(CH3)2, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R2 is not xe2x80x94CH(CH3)2 
when R1 is pyrid-3-yl, R2 is ethyl, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R3 is not xe2x80x94CH2CH(CH3)2,
when R1 is indoxazin-3-yl, 2,4-dimethylthiazol-5-yl, 4-methyl-1,2,5-thiooxadizol-3-yl or 3,5-di(trifluoromethyl)phenyl, R2 is methyl, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R3 is not xe2x80x94CH2CH(CH3)2, and
when R1 is xe2x80x94CH2-phenyl, R3 is xe2x80x94CH2CH3, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R2 is not xe2x80x94CH2CH(CH3)2.
Surprisingly, the substituents at the 2 and/or 6 positions of the phenyl group are limited to those recited above and larger substituents, other than those specifically specified above, eliminate the ability of the resulting compounds to inhibit xcex2-amyloid peptide release and/or its synthesis.
Accordingly, in one of its method aspects, this invention is directed to a method for inhibiting xcex2-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I above effective in inhibiting the cellular release and/or synthesis of xcex2-amyloid peptide.
Because the in vivo generation of xcex2-amyloid peptide is associated with the pathogenesis of AD8,9, the compounds of formula I can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, in another of its method aspects, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
In yet another of its method aspects, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
In formula I above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
Preferred R1 substituted aryl groups include, for example, monosubstituted phenyls having a single substitution at the 2, 3 or 4 positions where each of the particular subsituents is governed by the respective Ra/Raxe2x80x2, Rb/Rbxe2x80x2 and Rc groups; disubstituted phenyls which include those having two substituents at the 2,3-positions, 2,4-positions, 2,5-positions, 2,6positions, 3,4-positions, 3,5-positions or 3,6-positions where each of these substituents is governed by the respective Ra, Raxe2x80x2, Rb, Rbxe2x80x2 and RC groups; and trisubstituted phenyls which include those having three substituents at the 2,3,4-positions, 2,3,5-positions, 2,3,6-positions, 3,4,5-positions and 3,4,6-positions again where each of these substituents is governed by the respective Ra, Raxe2x80x2, Rb, Rbxe2x80x2 and Rc groups. Preferably, the substituted phenyl groups do not include more than 3 substituents.
Examples of substituted phenyls include, for instance, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-fluorophenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, and 2,5-difluorophenyl.
Preferred R1 groups represented by phenyl-R- include, by way of example, benzyl, 3-phenylethyl, 4-phenyl-n-propyl, and the like.
Preferred R1 alkyl, alkcycloalkyl, cycloalkyl and cycloalkenyl groups include, by way of example, sec-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, and the like.
Preferred R1 heteroaryls and substituted heteroaryls include, by way of example, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, benzothiazol4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, benzothiophen-3-yl, 2chlorothien-5-yl, 3-methylisoxazol-5-yl, 2-(phenylthio)thien-5-yl, 6methoxythiophen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.
Preferably R2 is selected from the group consisting of alkyl of from 1 to 4 carbon atoms, phenyl, alkylalkoxy of from 1 to 4 carbon atoms and alkylthioalkoxy of from 1 to 4 carbon atoms. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, xe2x80x94CH2CH2SCH3, cyclohexyl and phenyl.
When X is oxygen, preferred R3 substituents include, for example, methyl, ethyl, iso-propyl, n-propyl, n-butyl, iso-butyl, cyclopentyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-(3-tetrahydrofurany), xe2x80x94CH2-thien-2-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thien-3-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2]COOCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90C(CH3)2 and the like.
When X is sulfur, preferred R3 substituents include, for example, iso-but-2-enyl and iso-butyl.
This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and a compound of the formula I above.
Particularly preferred compounds for use in the methods and compositions of this invention include, by way of example, the following wherein the stereochemistry of the R2 group (where appropriate) is preferably derived from the L-amino acid:
N-(phenylacetyl)alanine iso-butyl ester
N-(3-phenylpropionyl)alanine iso-butyl ester
N-(3-methylpentanoyl)alanine iso-butyl ester
N-[(4-chlorophenyl)acetyl]alanine iso-butyl ester
N-[(3,4-dichlorophenyl)acetyl]alanine iso-butyl ester
N-[(3-pyridyl)acetyl]alanine iso-butyl ester
N-[(1-naphthyl)acetyl]alanne iso-butyl ester
N-[(2-naphthyl)acetyl]alanine iso-butyl ester
N-(4-phenylbutanoyl)alanine iso-butyl ester
N-(5-phenylpentanoyl)alanine iso-butyl ester
N-[(4-pyridyl)acetyl]alanine iso-butyl ester
2-[(3,4-dichlorophenyl)acetamido]butyric acid iso-butyl ester
2-[(3-methoxyphenyl)acetamido]butyric acid iso-butyl ester
2-[(4-nitrophenyl)acetamido]butyric acid iso-butyl ester
2-[(3,4-methylenedioxyphenyl)acetamido]butyric acid iso-butyl ester
2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester
2-[(4-chlorophenyl)acetamido]butyric acid iso-butyl ester
2-[(3-nitrophenyl)acetamido]butyric acid iso-butyl ester
2-[(2-hydroxyphenyl)acetamido]butyric acid iso-butyl ester
2-[(2-naphthyl)acetamido]butyric acid iso-butyl ester
2-[(2,4-dichlorophenyl)acetamid]butyric acid iso-butyl ester
2-[(4-bromophenyl)acetamido]butyric acid iso-butyl ester
2-[(3-chlorophenyl)acetamido])butyric acid iso-butyl ester
2-[(3-fluorophenyl)acetamido]butyric acid iso-butyl ester
2-[(Qenzothiazol-4-yl)acetamido]butyric acid iso-butyl ester
2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester
2-[(2-fluorophenyl)acetamido]butyric acid iso-butyl ester
2-[(4-fluorophenyl)acetamido]butyric acid iso-butyl ester
2-[(3-bromophenyl)acetamido]butyric acid iso-butyl ester
2-[(3-trifluoromethylphenyl)acetamido]butyric acid iso-butyl ester
2-[(2-thienyl)acetamido]butyric acid iso-butyl ester
2-(phenylacetamido)butyric acid iso-butyl ester
N-(phenylacetyl)valine 2-methylbutyl ester
N-(phenylacetyl)methionine iso-butyl ester
N-(phenylacetyl)leucine iso-butyl ester
N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl ester
N-[(3-chlorophenyl)acetyl]alanine cyclopropylmethyl ester
N-[(3-chlorophenyl)acetyl]alanine 2-thienylmethyl ester
N-[(3-chlorophenyl)acetyl]alanine (1-methylcyclopropyl)methyl ester
N-[(3-chlorophenyl)acetyl]alanine 3-thienylmethyl ester
N-[(3-chlorophenyl)acetyl]alanine 2-methylcyclopentyl ester
N-[(3-chlorophenyl)acetyl]alanine 2-methylprop-2-enyl ester
N-[(3-chlorophenyl)acetyl]alanine cyclohex-2-enyl ester
N-[(2-phenylbenzoxazol-5-yl)acetyl]alanine iso-butyl ester
N-[(3-methylthiophenyl)acetyl]alanine iso-butyl ester
N-4-[(2-furyl)acetyl]alanine iso-butyl ester
N-[(benzofuran-2-yl)acetyl]alanine iso-butyl ester
N-[(benzothiophen-3-yl)acetyl]alanine iso-butyl ester
N-[(2-chloro-5-thienyl)acetyl]alanine iso-butyl ester
N-[(3-methyl-isoxazol-5-yl)acetyl]alanine iso-butyl ester
N-[(2-phenylthiothienyl)acetyl]alanine iso-butyl ester
N-[(6-methoxybenzothiophen-2-yl)acetyl]alanine iso-butyl ester
N-[(3-phenyl-1,2,4-thiadiazol-5-yl)acetyl]alanine iso-butyl ester
N-[(2-phenyloxazol-4-yl)acetyl]alanine iso-butyl ester
N-[(3-methylphenyl)acetyl]alanine iso-butyl ester
N-[(2,5-difluorophenyl)acetyl]alanine iso-butyl ester
N-[(3,5-diflurophenyl)acetyl]alanine iso-butyl ester
N-[(3-thienyl)acetyl]alanine iso-butyl ester
N-[(4-methylphenyl)acetyl]alanine iso-butyl ester
N-(phenylacetyl)alanine (1-methoxycarbonyl)iso-butyl ester
N-[(3-nitrophenyl)acetyl]alanine iso-butyl ester
N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester
N-[(3-nitrophenyl)acetyl]methionine ethyl ester
N-[(3chlorophenyl)acetyl]alanine iso-butyl ester
N-[(3-chlorophenyl)acetyl]alanine 2-(N,N-dimethylamino)ethyl ester
2-[(3,5-dichlorophenyl)acetamido]hexanoic acid methyl ester
N-[(3,5dichlorophenyl)acetyl]alanine iso-butyl ester
N-(cyclohexylacetyl)alanine iso-butyl ester
N-(cyclopentylacetyl)alanine iso-butyl ester
N-[(cyclohex-1-enyl)acetyl]alanine iso-butyl ester
N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl thioester
N-[(2-phenyl)-2-fluoroacetyl]alanine ethyl ester
N-(3,5-difluorophenylacetyl)phenylglycine methyl ester
N-(3,5-difluorophenylacetyl)phenylglycine iso-butyl ester
N-(cyclopentylacetyl)phenylglycine methyl ester
N-(cyclopentylacetyl)alanine methyl ester
N-(cyclopropylacetyl)phenylglycine methyl ester
N-(cyclopropylacetyl)alanine methyl ester
N-[(3-nitrophenyl)acetyl]methionine iso-butyl ester
Still further, this invention provides for novel compounds of the formula III: 
wherein R1 is selected from the group consisting of
a) alkyl, alkenyl, alkcycloalkyl, phenyl-(R)m-, naphthyl-(R)m- wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1, cycloalkyl, cycloalkenyl, 3-pyridyl, 4-pyridyl and heteroaryl, other than 3- and 4-pyridyl, of 3 to 10 atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen wherein the heteroaryl group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy with the proviso that for such heteroaryls when there is at least one nitrogen heteroatom, there is also at least one oxygen and/or sulfur heteroatom;
(b) a substituted phenyl group of formula II: 
wherein R is alkylene of from 1 to 8 carbon atoms,
m is an integer equal to 0 or 1,
Ra and Raxe2x80x2 are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl;
Rb and Rbxe2x80x2 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cyano, cycloalkyl, halo, heteroaryl, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and xe2x80x94C(O)R4 where R4 is selected from the group consisting of alkyl, aryl, alkoxy and aryloxy; and
Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and where Rb and Rc are fusee to form a methylenedioxy ring with the phenyl ring; and
when Rb and/or Rbxe2x80x2 and/or Rc is fluoro, chloro, bromo and/or nitro, then Ra and/or Raxe2x80x2 can also be chloro; and
(c) 1- or 2-naphthyl-(R)m- wherein R is an alkylene group of from 1 to 8 carbon atoms and m is an integer equal to 0 or 1 substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy;
R2 is selected from the group consisting of hydrogen, alkyl, phenyl, alkylalkoxy, alkylthioalkoxy; and
R3 is selected from the group consizing of xe2x80x94(CH2)nCR10R5R6 wherein n is an integer equal to 0, 1 or 2, R5 and R6 are independently selected from hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, xe2x80x94NR7R8 where R7 and R8 are independently hydrogen or alkyl, and xe2x80x94COOR9 where R9 is alkyl, and further wherein R5 and R6 can be joined to form a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, and a heterocyclic group, and when R5 and R6 do not join to form an aryl or heteroaryl group, then R10 is selected from hydrogen and alkyl with the proviso that when n is zero, then R10 is hydrogen and and when n is greater than zero and R5 and R6 are joined to form an aryl or heteroaryl group, then R0 becomes a bond within that group;
X is oxygen or sulfur;
Xxe2x80x2 is hydrogen, hydroxy or fluoro;
Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group, and
pharmaceutically acceptable salts thereof
with the provisos that:
when R1 is phenyl, R2 is xe2x80x94CH(CH3)CH2CH3, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R3 is not xe2x80x94CH2CH3 or xe2x80x94CH2CH(CH3)2 
when R1 is phenyl, R3 is xe2x80x94CH2CH(CH3)2, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R2 is not xe2x80x94CH(CH3)2 
when R1 is pyrid-3-yl, R2 is ethyl, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R3 is not xe2x80x94CH2CH(CH3)2,
when R1 is indoxazin-3-yl, 2,4-dimethylthiazol-5-yl, 4-methyl-1,2,5-thiooxadizol-3-yl or 3,5-di(trifluoromethyl)phenyl, R2 is methyl, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R3 is not xe2x80x94CH2CH(CH3)2, and
when R1 is xe2x80x94CH2-phenyl, R3 is xe2x80x94CH2CH3, X is oxygen, and Xxe2x80x2 and Xxe2x80x3 are hydrogen, then R2 is not xe2x80x94CH2CH(CH3)2;
and still with further proviso excluding the following known compound: N-(phenylacetyl)methionine ethyl ester.
Preferred compounds of formula III above include those set forth in Formula IV below:
Another preferred compound of formula I above includes the compound wherein R1 is phenyl, R2 is fluoro and R3 is methyl.
As above, this invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease. However, prior to describing this invention in further detail, the following terms will first be defined.
DEFINITIONS
The term xe2x80x9cxcex2-amyloid peptidexe2x80x9d refers to a 3943 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al.1 including mutations and post-translational modifications of the normal xcex2-amyloid peptide. In whatever form, the xcex2-amyloid peptide is approximately a 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the xcex2-amyloid precursor protein (APP). Its 43-amino acid sequence is:
or a sequence which is substantially homologous thereto.
xe2x80x9cAlkylxe2x80x9d refers to monovalent alkyl groups preferably having from 1 to carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyi, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl, and the like.
xe2x80x9cAlkylenexe2x80x9d refers to divalent alkylene groups preferably having from 1 to 8 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94) and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkyl-Oxe2x80x94xe2x80x9d wherein alkyl is as defined herein. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cAlkylalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-O-alkylxe2x80x9d wherein alkylene and alkyl are as defined herein. Such groups include, by way of example, methylenemethoxy (xe2x80x94CH2OCH3), ethylenemethoxy (xe2x80x94CH2CH2OCH3), n-propylene-iso-propoxy (xe2x80x94CH2CH2CH2OCH(CH3)2), methylene-tert-butoxy (xe2x80x94CH2xe2x80x94Oxe2x80x94C(CH3)3) and the like.
xe2x80x9cAlkylthioalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-S-alkylxe2x80x9d wherein alkylene and alkyl are as defined herein. Such groups include, by way of example, methylenethiomethoxy (xe2x80x94CH2SCH3), ethylenethiomethoxy (xe2x80x94CH2CH2SCH3), n-propylene-iso-thiopropoxy (xe2x80x94CH2CH2CH2SCH(CH3)2), methylene-tert-thiobutoxy (xe2x80x94CH2SC(CH3)3) and the like.
xe2x80x9cAlkenylxe2x80x9d refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), iso-propenyl (xe2x80x94C(CH3)xe2x95x90CH2), and the like.
xe2x80x9cAlkynylxe2x80x9d refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH) and the like.
xe2x80x9cAcylxe2x80x9d refers to the groups alkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, and heteroaryl-C(O)xe2x80x94 where alkyl, aryl and heteroaryl are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen or alkyl.
xe2x80x9cAlkcycloalkylxe2x80x9d refers to the group -alkylene-cycloalkyl wherein alkylene and cycloalkyl are as defined herein.
xe2x80x9cAminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen or alkyl.
xe2x80x9cAcyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, and heterocyclic-C(O)Oxe2x80x94 where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, aryl, aryloxy, carboxyl, carboxylalkyl, acylamino, cyano, halo, nitrn, heteroaryl, trihalomethyl, thioalkoxy, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
xe2x80x9cAryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
xe2x80x9cCarboxylalkylxe2x80x9d refers to the group xe2x80x94C(O)O-alkyl where alkyl is as defined herein.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either fluoro or chloro.
xe2x80x9cHeteroarylxe2x80x9d refers to a monovalent aromatic group of from 2 to 8 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl and furyl.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a monovalent (i.e. one point of attachment) saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituernt, such heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy and the like. Such heterocyclic groups can have a single ring (e.g., piperidinyl or tetrahydrofuryl) or multiple condensed rings (e.g., indolinyl, dihydrobenzofuran or quinuclidinyl). Preferred heterocycles include piperidinyl, pyrrolidinyl and tetrahydrofuryl.
Examples of heterocycles and heteroaryis include, but are not limited to, furan, thiophene, thiazole, oxazole, benzothiazole, benzofuran, benzothiophene, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, pyrrolidine, indoline and the like.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkoxyxe2x80x9d refers to the groups -S-alkyl where alkyl is as defined herein.
xe2x80x9cThioaryloxyxe2x80x9d refers to the group aryl-Sxe2x80x94 wherein the aryl group is as defined above including opticnally substituted aryl groups as also defined above.
xe2x80x9cThioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
Compound Preparation
The compounds of formula I above are readily prepared via several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, the commercial availability of starting materials, and the like.
A first synthetic method involves conventional coupling of an acetic acid derivative with a primary amine of an esterified amino acid as shown in reaction (1): 
wherein R1, R2, R3, X, Xxe2x80x2 and Xxe2x80x3 are as defined above.
Reaction (1) merely involves coupling of a suitable acetic acid derivative 1 with the primary amine of amino acid ester 2 under conditions which provide for the N-acetyl derivative 3. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters 3 of this invention. For example, well known coupling reagents such as carboduimides or BOP (benzotriazol-1-yloxy-tris(dimethylamnino)plhosphonium hexafluorphosphate) with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrrhydrofuran and the like. Alternatively, the acid halide of compound 1 can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
Reaction (1) is preferably conducted at from about 0xc2x0 C. to about 60xc2x0 C. until reaction completion which typically occurs within 1 to about 24 hours. Upon reaction completion, N-acetyl amino acid ester 3 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
In reaction (1), each of the reagents (acetic acid derivative I and amino acid ester 2) are well known in the art with a plurality of each being commercially available.
Alternatively, the synthesis described above in reaction (1) can be conducted on the amino acid (X3xe2x95x90OH) and subsequent to N-acetyl formation as described above, the carboxylic acid is then esterified with either the alcohol (HOR3) or the thioalcohol (HSR3) under conventional conditions to provide for the N-acetyl amino acid ester 3 which is a compound of formula I. For example, esterification procedures for R3 groups containing an ester group can be achieved by using the methods of Losse, et al.10 
In still a further embodiment, conventional transesterification techniques can be used to prepare a variety of different ester groups on the N-acetyl amino acid esters 3. Numerous techniques are known in the art to effect transesterification and each technique merely replaces the xe2x80x94OR3 group on the ester of the N-acetyl amino acid ester 3 with a different xe2x80x94OR3/xe2x80x94SR3 group derived from the corresponding alcohol (i.e., HOR3) or thioalcohol (i.e., HSR3) and, in some cases, a catalyst such as titanium (IV) iso-propoxide is used to facilitate reaction completion. In one technique, the alcohol HOR3 or thioalcohol HSR3 is first treated with sodium hydride in a suitable diluent such as toluene to form the corresponding sodium alkoxide or thioalkoxide which is then employed to effect transesterification with the N-acetyl amino acid ester 3. The efficiency of this technique makes it particularly useful with high boiling and/or expensive alcohols.
In another transesterification technique, the N-acetyl amino acid ester 3 to be transesterified is placed in a large excess of the alcohol or thioalcohol which effects transesterification. A catalytic amount of sodium hydride is then added and the reaction proceeds quickly under conventional conditions to provide the desired transesterified product. Because this protocol requires the use of a large excess of alcohol or thioalcohol, this procedure is particularly useful when the alcohol is inexpensive.
Transesterification provides a facile means to provide for a multiplicity of R3 substituents on the compounds of formula I above. In all cases, the alcohols and thioalcohols employed to effect transesterification are well known in the art with a significant number being commercially available.
Other methods for preparing the esters of this invention include, by way of example, first hydrolyzing the ester to the free acid followed by O-alkylation with a halo-R3 group in the presence of a base such as potassium carbonate.
The compounds described herein can also be prepared by use of polymer supported forms of carbodiimide peptide coupling reagents. A polymer supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993))15. Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of the compounds of the present invention.
Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled in the polymer arts. A suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group. Additionally, the polymer""s backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used.
Certain hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents. Examples of these hydroxylated resins include the 4-hydroxymethyl-phenylacetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Ky., USA (see Advanced Chemtech 1993-1994 catalog, page 115). The hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan.
Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield""s resins and are available from Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich 1994-1995 catalog, page 899). Methods for the preparation of PEPC and its polymer supported forms are outlined in the following scheme. 
Such methods are described more fully in U.S. Provisional Patent Application 60/019,790, filed Jun. 14, 1996, the disclosure of which is incorporated herein by reference in its entirety. Briefly, PEPC is prepared by first reacting ethyl isocvanate with 1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
The carboxylic acid coupling reactions employing these reagents are performed at about ambient temperature to about 45xc2x0 C., for from about 3 to 120 hours. Typically, the product may be isolated by washing the reaction with CHCl3 and concentrating the remaining organics under reduced pressure. As discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
Still other methods for the preparation of esters are provided in the examples below.
In these synthetic methods, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enantiomers. Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols can involve inversion of the chiral center during synthesis.
Accordingly, unless otherwise indicated, the products of this invention are a mixture of R,S enantiomers. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. Alternatively, chiral products can be obtained via purification techniques which separate enantiomers from a R,S mixture to provide for one or the other stereoisomer. Such techniques are well known in the art.
Pharmaceutical Formulations
When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner Yell known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivtded into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, oI powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The following formulation examples illustrate representative pharmaceutical compositions of the present invention.